The ability to respond to stress is an important basic adaptive mechanism, and hypothalamic-pituitary-adrenal (HPA) activation is a central component of this response. In the short term, stress-induced increases in corticosteroids (CORT) enable the organism to respond to and cope with the stressor. However, prolonged HPA activation can result in adverse physiological and behavioral consequences that can compromise health and even survival. Therefore, early life events that result in greater reactivity to stress and a lifetime of increased levels of CORT can increase the vulnerability to illnesses later in life. Our data demonstrate that 1) prenatal ethanol (E) exposure reprograms the fetal HPA axis and the central components that regulate HPA activity such that HPA tone is increased throughout life; 2) the change in set point of HPA activity appears to be mediated by alterations at multiple levels of the axis and under both basal and stress conditions; 3) E males and females show different patterns of response to stressors, indicating a marked sexual dimorphism in fetal ethanol effects and a possible role for the gonadal steroids in mediating HPA hyperresponsiveness. It appears that the balance between HPA drive and feedback is differentially altered in E males and females. A change in the balance between drive and feedback impairs the ability to maintain homeostasis, and progressively creates a condition of disturbed neuroendocrine regulation and behavioral adaptation. In turn, these changes have implications for vulnerability to illnesses, as noted, and for the development of secondary disabilities such as mental health and behavior problems in children with FAS. The proposed research will continue our study of the mechanisms underlying HPA dysregulation in E animals, and will extend our focus to an examination of mechanisms underlying the sex differences observed. The Specific Aims are: 1) to investigate further the mechanisms underlying the increased HPA responsiveness and altered HPA regulation observed in E animals; and 2) to investigate the modulatory influences of the gonadal steroids in the differential HPA responsiveness of E males and females compared to their control counterparts. The data from these studies will significantly advance our understanding of the long term and far reaching consequences of prenatal ethanol exposure on health and well-being, and will have important implications for the development of interventions and treatments.